Inhibitors of acyl-coenzyme A: cholesterol acyl transferase

ABSTRACT

Amides of the formula ##STR1## wherein R 1  and R 2  are independently heteroaryl, X-substituted heteroaryl, X-substituted phenyl, N-substituted triazinyl or N-substituted imidazolyl; 
     and in addition, one of R 1  and R 2  can be as defined above and the other can be phenyl; 
     R 3  is an alkyl chain of 2 to 25 carbon atoms, saturated or unsaturated; an alkyl chain as defined substituted by one or more substituents selected from the group consisting of phenyl, X-substituted phenyl, heteroaryl and X-substituted heteroaryl; an alkyl chain as defined interrupted by one or more groups independently selected from the group consisting of --O--, --S--, --SO--, --SO 2  --, --NH--, --N(lower alkyl)--, --C(O)--, phenylene, X-substituted phenylene, heteroarylene and X-substituted heteroarylene; or an interrupted alkyl chain as defined substituted by one or more substituents selected from the group consisting of phenyl, X-substituted phenyl, heteroaryl and X-substituted heteroaryl; 
     R 4  is hydrogen, lower alkyl, phenyl, X-substituted phenyl, heteroaryl or X-substituted heteroaryl; or a pharmaceutically acceptable salt thereof, useful as inhibitors of acyl-coenzyme A:cholesterol acyl transferase and therefore in the treatment of atherosclerosis are disclosed.

BACKGROUND OF THE INVENTION

The present invention relates to 1,2-disubstituted ethyl amides usefulin the treatment and prevention of atherosclerosis.

Atherosclerotic coronary heart disease represents the major cause fordeath and cardiovascular morbidity in the western world. Risk factorsfor atherosclerotic coronary heart disease include hypertension,diabetes mellitus, family history, male sex, cigarette smoking and serumcholesterol. A total cholesterol level in excess of 225-250 mg/dl isassociated with significant elevation of risk.

Cholesterol esters are a major component of atherosclerotic lesions andthe major storage form of cholesterol in arterial wall cells. Formationof cholesterol esters is also a key step in the intestinal absorption ofdietary cholesterol. The intracellular esterification of cholesterol iscatalyzed by the enzyme acyl CoA:cholesterol acyl transferase (ACAT, EC2.3.1.26). Thus, inhibition of ACAT is likely to inhibit the progressionof atherosclerotic lesion formation, decrease the accumulation ofcholesterol esters in the arterial wall, and block the intestinalabsorption of dietary cholesterol.

A number of amides have been reported as being useful in loweringcholesterol and/or in inhibiting the formation of cholesterol-containinglesions in mammalian arterial walls. U.S. Pat. No. 3,784,577 toFukurmaru et al discloses fatty acid amide derivatives of the formulaR--CONHR¹ wherein RCO is a fatty acid radical and R¹ is1-α-benzylbenzyl.

U.S. Pat. No. 4,603,145 to De Vries et al discloses diaryl alkanamidesof the formula ##STR2## wherein R³ and R⁴ independently include benzyland phenethyl.

U.S. Pat. No. 4,420,475 to Damon et al discloses silicon-bearing amidesof the formula ##STR3## wherein R¹, R² and R³ independently can bealkyl, phenyl, benzyl or phenethyl and R can be 1-α-benzylbenzyloptionally substituted in the phenyl rings. U.S. Pat. No. 4,434,161 toBarcza discloses similar compounds having a sulfur atom in the chainbetween the silicon atom and the carbonyl group.

U.S. Pat. No. 4,456,619 to Kathawala discloses amides of 2-alkynoicacids of the formula ##STR4## wherein A is alkyl, alkenyl orcyclopropanyl-substituted alkyl and B can be 1-α-benzylbenzyl,optionally substituted in the phenyl rings.

U.S. Pat. No. 4,716,175 to Hoefle et al discloses fatty acid amides ofthe formula ##STR5## wherein A is an alkyl chain, R¹ and R² can each bephenylmethyl, and B can be phenyl, benzyl, pyrimidinyl or pyridyl.

U.S. Pat. No. 4,518,789 to Yu et al discloses dermatologically usefulphenyl alpha-acyloxyacetamides of the formula ##STR6## wherein R¹ and R²can be hydrogen, alkyl or aralkyl and R³ and R⁴ can be hydrogen, alkyl,aralkyl or aryl.

While some of these diphenylethylamides have shown in vitro ACATinhibitory activity, none have been reported to show significantactivity in whole animal models of atherosclerosis.

SUMMARY OF THE INVENTION

Novel compounds of the present invention which show significant in vivoatherosclerotic activity are represented by the formula ##STR7## whereinR₁ and R₂ are independently a heteroaryl group selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, triazinyl,imidazolyl, thiophenyl, oxazolyl and furanyl; X-substituted heteroarylwherein X is 1 to 3 substituents independently selected from the groupconsisting of halogeno, lower alkyl, hydroxy, lower alkoxy, amino, loweralkylamino, lower dialkylamino, acetamido, methanesulfonyl-amino,2-(trimethylsilyl)ethoxymethyl, carboxy and lower alkoxycarbonyl;X-substituted phenyl; or N-substituted triazinyl or N-substitutedimidazolyl wherein the N-substituents are selected from the groupconsisting of lower alkyl, 2-(trimethylsilyl)ethoxymethyl and R₅ CO--wherein R is lower alkyl, phenyl, benzyl or 2,2-dimethylpropyl;

and in addition, one of R₁ and R₂ can be as defined above and the othercan be phenyl;

R₃ is an alkyl chain of 1 to 25 carbon atoms, branched or straight,saturated or containing one or more double bonds; an alkyl chain asdefined substituted by one or more substituents selected from the groupconsisting of phenyl, X-substituted phenyl, heteroaryl and X-substitutedheteroaryl; an alkyl chain as defined interrupted by one or more groupsindependently selected from the group consisting of --O--, --S--,--SO--, --SO₂ --, --NH--, --N(lower alkyl)--, --C(O)--, phenylene,X-substituted phenylene, heteroarylene and X-substituted heteroarylene;or an interrupted alkyl chain as defined substituted by one or moresubstituents selected from the group consisting of phenyl, X-substitutedphenyl, heteroaryl and X-substituted heteroaryl;

R₄ is hydrogen, lower alkyl, phenyl, X-substituted phenyl, heteroaryl orX-substituted heteroaryl; or a pharmaceutically acceptable salt thereof.

Preferred are compounds of formula I wherein R₁ is amino-substitutedphenyl and R₂ is phenyl.

Another group of preferred compounds is that wherein one of R₁ and R₂ islower alkoxy-substituted phenyl and the other is phenyl, or each of R₁and R₂ is lower alkoxy-substituted phenyl, preferably wherein loweralkoxy is methoxy.

Also preferred are compounds wherein one of R₁ and R₂ ishydroxy-substituted phenyl and the other is phenyl, or each of R₁ and R₂is hydroxy-substituted phenyl.

Still another group of preferred compounds is that wherein one of R₁ andR₂ is a hetereroaryl group and the other is phenyl. Preferredhetereroaryl groups are pyridyl, quinolyl and imidazolyl.

Yet another group of preferred compounds is that wherein one of R₁ andR₂ is carboxy-substituted phenyl or lower alkoxycarbonyl-substitutedphenyl and the other is phenyl.

Also preferred are compounds of formula I wherein R₃ is adiphenyl-substituted alkyl chain, especially diphenylmethyl ordiphenylethyl (i.e. --C(O)R₃ is diphenylacetyl or2,3-diphenylpropanoyl), or CH₃ (CH₂)₇ CH═CH(CH₂)₇ -- (i.e. --C(O)R₃ isoleoyl). A preferred substituent for R₄ is hydrogen.

Especially preferred are compounds of formula I wherein R₁ isamino-substituted phenyl, R₂ is phenyl, R₃ is diphenylmethyl or CH₃(CH₂)₇ CH═CH(CH₂)₇ -- and R₄ is hydrogen.

This invention also relates to the use of the ACAT inhibitors of thepresent invention as hypolipidemic and hypocholesterolemic agents inmammals.

In another aspect, the invention relates to pharmaceutical compositionscomprising an ACAT inhibitor of the present invention in apharmaceutically acceptable carrier.

DETAILED DESCRIPTION

As used herein, the term "lower alkyl" means straight or branched alkylchains of 1 to 6 carbon atoms and "lower alkyoxy" similarly refers toalkoxy groups having 1 to 6 carbon atoms.

Halogeno refers to fluorine, chlorine, bromine or iodine radicals.

"Phenylene" means a bivalent phenyl group, including ortho, meta andpara-substitution and "heteroarylene" similarly means a bivalentheteroaryl group.

Where R₁ or R₂ is a heteroaryl group containing a secondary amino group(e.g. triazinyl or imidazolyl), the R₁ or R₂ heteroaryl group can beattached to the rest of the molecule either by a ring carbon or by thesecondary amino group (e.g. 1-imidazolyl or 2-imidazolyl). Also, if itis not the point at which the ring is attached to the molecule, thesecondary amino group can be substituted with a substituent selectedfrom the group consisting of lower alkyl,2-(trimethylsilyl)ethoxymethyl, and R₅ CO-- wherein R₅ is lower alkyl,phenyl, benzyl or 2,2-dimethylpropyl.

The alkyl chain as defined in R₃ can be a radical of a synthetic ornatural fatty acid, either saturated or containing one or more carbon tocarbon double bonds, or can be an interrupted alkyl chain wherein one ormore of the carbon atoms in the chain can be replaced by an --O--,--S--, --SO--, --SO₂ --, --NH--, --N(lower alkyl)--, --C(O)--, phenyleneor heteroarylene group. When substituted by optionally substitutedphenyl or heteroaryl groups, the alkyl chain or interrupted alkyl chainmay be independently substituted on different carbon atoms,di-substituted on one carbon atoms, or both.

One skilled in the art will recognize that the number of double bondspresent, the replacement of carbon atoms in the chain and the presenceof substituents on the carbon atoms in the chain are all dependent onthe length of the chain: shorter alkyl chains cannot accommodate as manybonds, carbon replacements or substituents as longer alkyl chains. Ingeneral, unsaturated alkyl chains contain 1 to 4 double bonds,conjugated or non-conjugated. Where carbon atoms are replaced, 1 to 4replacement groups can be present. Similarly, when carbon atoms in thechain are substituted, 1 to 4 substituents can be present.

Examples of alkyl chains are as follows, wherein the group --C(O)R₃ isnamed: palmitoyl, 2,2-dimethylpalmitoyl, caproyl, capryloyl, stearoyl,dodecanoyl, and 2,2-dimethyldodecanoyl.

Examples of unsaturated --C(O)R₃ groups are oleoyl, 2,2-dimethyloleoyl,linoleoyl, linolenoyl, elaidoyl, eicosatetraenoyl, and eicosapentaenoyl.

Examples of --C(O)R₃ groups wherein the carbon atoms are substituted arephenylacetyl and those having the formula --C(O)CH(C₆ H₄ X)--(CH₂)_(n)--C₆ H₄ X wherein X is hydrogen or is as defined above and n is 0 to 10,for example diphenylacetyl, 2,2-diphenylpropanyl, anddi-(4-chlorophenyl)acetyl or 2,3-diphenylpropanyl.

Examples of --C(O)R₃ groups wherein carbon atoms in the chain arereplaced are: 3-methoxy-4-(tetradecyloxy)-benzoyl,11-[N-(2,2-diphenylacetyl)amino]undecanoyl and phenoxyundecanoyl.

Compounds of the invention have at least one asymmetrical carbon atomand therefore include rotational isomers. The invention includes d and Iisomers in both pure form and in admixture, including racemic mixtures.Isomers can be prepared using conventional techniques, either byreacting enantiomeric starting materials or by separating isomers of acompound of formula I.

Isomers may include geometric isomers, e.g. when R₃ contains a doublebond. All such isomers are contemplated for this invention.

Compounds of the invention with an amino group can form pharmaceuticallyacceptable salts with organic and inorganic acids. Examples of suitableacids for salt formation are hydrochloric, sulfuric, phosphoric, acetic,citric, oxalic, malonic, salicyclic, malic, fumaric, succinic, ascorbic,maleic, methanesulfonic and other mineral and carboxylic acids wellknown to those in the art. The salt is prepared by contacting the freebase form with a sufficient amount of the desired acid to produce asalt. The free base form may be regenerated by treating the salt with asuitable dilute aqueous base solution such as dilute aqueous sodiumbicarbonate. The free base form differs from its respective salt formsomewhat in certain physical properties, such as solubility in polarsolvents, but the salt is otherwise equivalent to its respective freebase forms for purposes of the invention.

Certain compounds of the invention are acidic (e.g., those compoundswhich possess a carboxyl group). These compounds form pharmaceuticallyacceptable salts with inorganic and organic bases. Examples of suchsalts are the sodium, potassium, calcium, aluminum, gold and silversalts. Also included are salts formed with pharmaceutically acceptableamines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like.

Compounds of formula I can be prepared under standard reactionconditions well known in the art. For example, a carboxylic acid offormula II can be converted to the acid chloride by treatment withthionyl or oxalyl chloride in a solvent such as dichloromethane, thenreacted with an amine of formula III in the presence of a tertiary aminebase such as triethylamine, 4-dimethylaminopyridine (DMAP) orN-methylmorpholine (NMM): ##STR8##

Alternatively, the acid of formula II and amine of formula III can bereacted in the presence of a coupling agent such asdicyclohexylcarbodiimide (DCC) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) and a base such astriethylamine, DMAP or NMM in a solvent such as dichloromethane or THFat a temperature of 0° to 23° C. In a third method, the carboxy group ofacid II can be activated via the intermediacy of an active ester such asthat derived from 1-hydroxybenzotriazole (HOBT).

Starting carboxylic acids of formula II are commercially available orcan be prepared by well known methods.

Amines of formula III can be prepared by several methods. In one method,an aldehyde of formula IV, either commercially available or easilyprepared by methods known in the art, is reacted with triethylphophiteand benzylcarbamate to obtain a phosphorane of formula V. Thephosphorane is then reacted with a second aldehyde of formula VI toobtain an enamine of formula VII. The enamine is reduced to the desiredamine by reaction with hydrogen gas at 50 psi in the presence of asuitable catalyst such as 10% palladium on carbon. The reaction schemeis shown below: ##STR9##

In a second method for preparing an amine of formula III, an aldehyde offormula IV is converted to an N-trimethylsilylimine of formula VIII byreaction with lithium hexamethyldisilazide. The compound of formula VIIIis then treated with a lithium reagent of formula IX to obtain the amineof formula III. The reaction scheme is as follows: ##STR10##

A third method for preparing amines of formula III comprises reaction ofa ketone of formula X with an amine of the formula NH₂ X, wherein X ishydroxy or R₄ as defined above, to obtain the corresponding imine offormula XI. The imine is reduced to the desired amine, for example byreaction with hydrogen gas at 50 psi in the presence of a suitablecatalyst such as 10% palladium on carbon or by reaction with zinc metalin a solvent such as acetic acid. The reaction scheme is shown asfollows: ##STR11##

The ketone of formula X may be prepared by several methods. For ketonesof formula Xa wherein R₂ is phenyl or substituted phenyl, a carboxylicacid chloride of formula XII can be reacted with a phenyl or substitutedphenyl derivative of formula XIII in the presence of a Lewis acid suchas aluminum chloride: ##STR12## wherein Y are the phenyl substituents asdefined in R₂ above. Alternatively, compounds wherein R₂ is phenyl orsubstituted phenyl can be prepared by reaction of a carboxylic acid offormula XIIa with a compound XIII in the presence of a strongdehydrating acid such as polyphosphoric acid or phosphorus pentoxide inmethanesulfonic acid: ##STR13##

Another method for preparing ketones of formula X comprises reacting anitrile of formula XIV with a carboxylic acid ester of formula XV in thepresence of an alkoxide base such as sodium ethoxide, then hydrolyzingand decarboxylating the product using a strong acid such as 48%hydrobromic acid: ##STR14##

For ketones of Formula Xb wherein R₁ is 1-imidazolyl, imidazole can bereacted with a bromoketone of formula XVI: ##STR15##

Reactive groups not involved in the above processes can be protectedduring the reactions with conventional protecting groups which can beremoved by standard procedures after the reaction. The following tableshows some typical protecting groups:

    ______________________________________                                        Group to be protected                                                                        Protected group                                                ______________________________________                                        COOH           COOalkyl, COObenzyl,                                                          COOphenyl                                                       ##STR16##                                                                                    ##STR17##                                                                     ##STR18##                                                                     ##STR19##                                                                     ##STR20##                                                     OH             OCH.sub.3                                                      NHQ wherein Q is any amino substituent defined above                                          ##STR21##                                                     NH.sub.2                                                                                      ##STR22##                                                     ______________________________________                                    

We have found that the compounds of this invention are inhibitors ofACAT in vitro and in whole animal models the compounds have been foundto significantly reduce the formation of liver cholesterol esters. Thus,compounds of this invention are hypocholesterolemic and hypolipidemicagents by virtue of their ability to inhibit the esterification andintestinal absorption of cholesterol; they are therefore useful in thetreatment and prevention of atherosclerosis in mammals, in particular inhumans.

In addition to the compound aspect, the present invention therefore alsorelates to a method of treating atherosclerosis, in particular byreducing serum cholesterol, which method comprises administering to amammal in need of such treatment a hypocholsterolemic effective amountof a compound of this invention. The compound is preferably administeredin a pharmaceutically acceptable carrier suitable for oraladministration.

The in vitro and in vivo activity of the present compounds can bedetermined by the following procedures.

ACAT Assay (in vitro)

This assay measures the activity of ACAT by measuring the ACAT-mediatedtransfer of tritiated oleic acid from acyl-CoA to cholesterol to givelabelled cholesterol oleate. Rat liver microsomes are used as the sourceof ACAT. Assays are performed in round bottom microtiterplates using atotal incubation volume of 50 μL. Each incubation well receives 10 μLassay buffer (0.5M KHPO₄, 10 μM dithiothreitol, pH 7.4), 7.5 μL of 40mg/mL BSA (Bovine Serum Albumin) and 12.5 μg of microsomal protein. Thetest compound (in sufficient amount to bring the final concentration tofrom 0.1 to 25 μM), reference compound, or vehicle control is added andthe final volume brought to 47 μL. The microtiterplate is then floatedon the surface of a 37° C. water bath for fifteen minutes. Incubationsare started by the addition of 3 μL ³ H-acyl CoA (1 μCi/well, finalconcentration of 10 μM acyl CoA). The plate is then returned to thewater bath for 15 minutes. The incubations are then terminated byapplication of 15 μL from each incubation to individual lanes on a thinlayer plate (Silica Gel GF 20×20 cm). Standards are applied to severallanes so that the cholesterol ester band can be identified. Afterdrying, the plates are eluted with 90:10:1 petroleum ether:diethylether:acetic acid. The standards are visualized via iodine vapor, andthe regions corresponding to cholesterol ester are scraped into 7 mLscintillation vials. 4 mL of scintillant are added to each vial, and theradioactivity quantified. Background count is determined by the boiledcontrols. Full activity is determined by activity in the presence ofvehicle. The percent inhibition is calculated by subtracting thebackground from both control and test samples, and the test value iscalculated as a percentage of the control. For IC₅₀ determinations, theinhibition is plotted against drug does on a log scale and theconcentration at which 50% inhibition is obtained is determined.

In Vivo Assay of Hypolipidemic Agents Using the Hyperlipidemic Hamster

Hamsters are separated into groups of six and given a controlcholesterol diet (Purina Chow #5001 containing 0.5% cholesterol) forseven days. Diet consumption is monitored to determine dietarycholesterol exposure in the face of test compounds. The animals aredosed with the test compound once daily beginning with the initiation ofdiet. Dosing is by oral gavage of 0.2 mL of corn oil alone (controlgroup) or solution (or suspension) of test compound in corn oil. Allanimals moribund or in poor physical condition are euthanized. Afterseven days, the animals are anesthetized by IM injection of ketamine andsacrificed by decapitation. Blood is collected into vacutainer tubescontaining EDTA for plasma lipid analysis and the liver excised fortissue lipid analysis. Data is reported as percent reduction of lipidversus control.

The present invention also relates to a pharmaceutical compositioncomprising a compound of this invention and a pharmaceuticallyacceptable carrier. The compounds of formula I can be administered inany conventional oral dosage form such as capsules, tablets, powders,cachets, suspensions or solutions. The formulations and pharmaceuticalcompositions can be prepared using conventional pharmaceuticallyacceptable excipients and additives and conventional techniques. Suchpharmaceutically acceptable excipients and additives include non-toxiccompatible fillers, binders, disintegrants, buffers, preservatives,anti-oxidants, lubricants, flavorings, thickeners, coloring agents,emulsifiers and the like.

The daily hypocholesteremic or hypolipidemic dose of a compound offormula I is about 7 to about 30 mg/kg of body weight per day. For anaverage body weight of 70 kg, the dosage level is therefore from about500 to about 2000 mg of drug per day, given in a single dose or 2-4divided doses. The exact dose, however, is determined by the attendingclinician and is dependent on the potency of the compound administered,the age, weight, condition and response of the patient.

Following are preparations of starting materials and examples ofpreparing compounds of formula I.

PREPARATION 1 1-(4-Aminophenyl)-2-Phenylethylamine

Step A; A mixture of 4-nitrobenzaldehyde (5.0 g), triphenylphosphite(8.53 g) and benzylcarbamate (4.16 g) in glacial acetic acid (5 mL) wasstirred at 75°-80° C. for 2 hr. The resulting thick solid was dissolvedin chloroform (80 mL) and methanol (320 mL) was added; the resultingcloudy solution was refrigerated overnight. The precipitate wascollected, washed with cold methanol, and vacuum-dried to give 9.45grams of crude product. This was crystallized from methanol:chloroform4:1 to give 8.28 grams of diphenyl2-[(4-nitrophenyl)-2-benzyloxycarbonylamino]methylphosphonate.

Step B; A solution of the above phosphonate (4.0 g) in 50 mL THF wascooled to -40° C. and 10% KOH in methanol (4.3 g) was added dropwiseover 30 minutes. The deep-purple solution was stirred for 90 minutes,after which a solution of benzaldehyde (10.89 g) in THF (10 mL) wasadded in portions while maintaining the reaction temperature at -30° to-40° C. After the addition was complete, the mixture was maintained at-40° C. for 20 minutes, then allowed to come to room temperature. Thesolvent was removed under vacuum and the residue was extracted intoethyl acetate. The ethyl acetate was then washed with water, aqueoussodium bicarbonate and with brine, dried over magnesium sulfate andevaporated. The residue was chromatographed over silica gel, elutingwith 20% ethyl acetate-hexane to give 1.80 of1-(4-nitrophenyl)-1-benzyloxycarbonylamino-2-phenylethylene.

Step C; A solution of the above product (0.50 g) in ethanol (70 mL) andmethanol (40 mL) was hydrogenated at 50 psi over 10% palladium on carbon(0.1 g) for two hours at room temperature. After filtering throughcelite, the solvent was evaporated to give 0.28 grams of the titlecompound.

PREPARATION 21-Phenyl-2-[1-[[2-(Trimethylsilyl)Ethoxy]Methyl]-1H-Imidazol-2-yl]Ethylamin

2-Methyl-1-[[(trimethylsilyl)ethoxy]methyl]imidazole (2.04 g) wasdissolved in dry THF (25 mL), cooled to -78° C. and treated witht-butyllithium (5.14 mL). The cooling bath was removed for 10 min., themixture was recooled to -78° C. and transferred via cannula to a -78° C.solution of N-trimethylsilylbenzaldimine (1.31 mL) (prepared by reactionof benzaldehyde with lithium hexamethyl-disilazide) in THF (25 mL). Thereaction was allowed to warm slowly to room temperature overnight (about18 hr.). The reaction was quenched with sat. ammonium chloride solutionand extracted with ethyl acetate (3×). The organic extracts werecombined and washed with brine (3×), dried over anhydrous sodiumsulfate, filtered through cotton and concentrated in vacuo. The oil waschromatographed on silica, eluting with 5% MeOH/CH₂ Cl₂ followed by 5%NH₄ OH (conc.)/5% MeOH/CH₂ Cl₂ to provide the title compound as an oil.¹ H NMR (300 MHz, CDCl₃): 7.34 (5H, m, Ar); 7.02 (1H, s, Im-H); 6.92(1H, s, Im-H); 5.02 (2H, q, J=11 Hz, NCH₂ O); 4.62 (1H, t, J=6.6 Hz,PhCHNH₂); 3.45 (2H, t, J=7.7 Hz, OCH₂ CH₂); 2.64 (2H, Bs, NH₂); 0.89(2H, app t, J=8.2 Hz, CH₂ CH₂ Si); -0.02 (9H, s, Si(CH3)₃). MS(Cl+/isobutane): 318(M+, 100).

PREPARATION 2A 2-[1-Heptyl-1H-Imidazol-2-yl]-1-Phenylethylamine

In a manner similar to that described in Preparation 2, treat2-methyl-1-heptylimidazole to obtain the title compound.

PREPARATION 3 2-(4-Aminophenyl)-1-Phenylethylamine

Step A; To a solution of 4-nitrophenylacetic acid (200 g) in benzene(1.5 L) was added oxalyl chloride (200 mL). The mixture was warmed to50°-60° C. for 2 hrs, after which time benzene and excess oxalylchloride were distilled off under vacuum at 50° C. until a final volumeof 500 mL was achieved. The residue was diluted with benzene (1 L) andcooled to 0° C. To this was added anhydrous aluminum chloride (160 g)portion-wise over 15 minutes. Thereafter, the mixture was stirredovernight at room temperature. The reaction mixture was poured over amixture of ice (3 L) and concentrated HCl (1 L). The resulting slurrywas filtered through celite and the precipitate washed with ethylacetate. The combined filtrates were washed with water, saturated sodiumbicarbonate and with brine, dried over sodium sulfate and evaporated togive 227 grams of 2-(4-nitrophenyl)-1-phenylethanone.

Step B; To a solution of the product of Step A (220 g) in pyridine (2.5L) at 0° C. was added hydroxylamine hydrochloride (70.0 g). The reactionmixture was stirred for 3.5 hours while coming slowly to roomtemperature. The reaction mixture was poured into water and extractedwith dichloromethane. The organic layer was washed with water, driedover sodium sulfate and evaporated. The crude product was filteredthrough a bed of silica gel, eluting with dichoromethane:hexane 2:1. Thesolvent was evaporated and the residue was crystallized fromether-hexane to give 160 grams of oxime. This was hydrogenated in two80-gram lots over 10% Pd/C at 50 psi in ethanol to give, afterfiltration and evaporation, 128 grams of the title compound.

PREPARATION 4 1-(4-Methoxyphenyl)-2-Phenylethylamine

Step A; A mixture of methanesulfonic acid (100 g) and P₂ O₅ (10 g) wasstirred at 50°-60° C. until solution was complete, then cooled to roomtemperature. To this was added phenylacetic acid (2.0 g) and anisole(4.00 g). The mixture was stirred at 50°-60° C. for 90 minutes, cooledto room temperature and poured into ice water (1.2 L). The solution wasmade basic by gradual addition of solid sodium bicarbonate, thenextracted into ethyl acetate (800 mL). The ethyl acetate was dried overmagnesium sulfate and evaporated to give 3.88 grams of crude product.This crude product was chromatographed on silica gel eluting with 2%ethyl acetate in hexane, to obtain 2.92 grams of1-(4-methoxyphenyl)-2-phenylethanone.

Step B; The product of Step A was treated in a manner similar to thatdescribed in Preparation 3, Step B, to obtain the title compound.

PREPARATION 5 1-(4-Pyridinyl)-2-Phenylethylamine

Step A; To a solution of sodium ethoxide (prepared from 2.56, sodiummetal) in ethanol (50 mL) was added isonicotinic acid (10.0 g) andphenylacetonitrile (8.54 g) and the mixture was heated at reflux for 2.5hours. After cooling to room temperature, the mixture was poured intoice water and brought to pH 3 by addition of concentrated HCl. Theresulting precipitate was collected, washed with water and dried undervacuum to give 13.6 grams of crude cyanoketone.

A solution of the above product (5.00 g) was suspended in 48% HBr (30mL) and the mixture heated at reflux for five hours. After cooling in anice bath, the mixture was made basic by addition of concentrated ammoniaand the mixture was extracted with two 200 mL portions of ethyl acetate.The combined organic layers were washed with water and with brine, driedover magnesium sulfate and evaporated to give 2.71 grams of1-(4-pyridinyl)-2-phenylethanone.

Step B; The product of Step A was treated in a manner similar to thatdescribed in Preparation 3, Step B, to obtain the title compound.

PREPARATION 6 2-(1-H-Imidazol-1-yl)-1-Phenylethylamine

To a solution of imidazole (5.88 g) in THF (100 mL) was added2-bromoacetophenone (6.84 g). After 1.5 hours, the mixture wastransferred to a separatory funnel, washed with saturated sodiumbicarbonate, water and with brine, dried over sodium sulfate andevaporated. The residue was passed through a short silica gel column,eluting with 10% methanol in dichloromethane to give 4.51 grams of ayellow solid.

Step B; The product of Step A was treated in a manner similar to thatdescribed in Preparation 3, Step B, to obtain the title compound.

PREPARATION 7 Resolution of 2-(4-Aminophenyl)-1-Phenylethylamine

Dissolve racemic 2-(4-aminophenyl)-1-phenylethylamine (10.0 g) fromPreparation 3 in ethanol (300 mL) with heating and add a solution ofdi-p-toluoyl-L-tartaric acid (18.2 g) in ethanol (150 mL). Heat theresulting suspension to reflux and add additional ethanol (1 L) untilthe suspension dissolves. Cool the solution to room temperature, thenrefrigerate for two days. Filter the resulting precipatate, wash withcold ethanol followed by ethyl acetate and dry under vacuum to give thetartrate salt of 2-(4-aminophenyl)-1-phenylethylamine. Crystallize againfrom hot ethanol (725 mL), then convert to the free base by stirringwith 1N NaOH solution. Extract the resulting oily suspension with ethylacetate, wash the ethyl acetate layer with water and with brine, dryover magnesium sulfate and evaporate to obtain a tan solid. Dissolve thesolid in dichloromethane and evaporate three times to obtain the pure(-) 2-(4-aminophenyl)-1-phenylethylamine, [α]D²⁶ =-56.01°(MeOH).

The (+) isomer can be similarly prepared by usingdi-p-toluoyl-D-tartaric acid.

EXAMPLE 1N-[2-(4-Aminophenyl)-1-Phenylethyl]-2,2-Dimethyl-9-Z-Octadecenamide

To a solution of 2-(4-aminophenyl)-1-phenylethylamine (0.155 g, 0.74mMol) in THF at 0° C. was added 2,2-dimethyloleoyl chloride (0.2 g, 0.61mMol) and the reaction mixture was stirred overnight while warming toroom temperature. The reaction was quenched by pouring the mixture intowater: saturated aqueous sodium bicarbonate (1:1). The resultantsolution was extracted into ethyl acetate, the organic layer was driedover magnesium sulfate and evaporated. The residue was purified bychromatography on silica gel, eluting with hexane:ethyl acetate(1:1) toobtain 0.240 mg of the title compound. FAB (M+1)=505. ElementalAnalysis: calc. for C₃₄ H₅₂ N₂ O is C=80.9%, H=10.38%, N=5.55%; foundC=81.1%, H=10.1%, N=5.43%.

Using a similar procedure, the following compounds can also be prepared:

    __________________________________________________________________________     ##STR23##                                                                    Compound #                                                                           R.sub.1  R.sub.2   R.sub.3        Physical Data                        __________________________________________________________________________    1A     C.sub.6 H.sub.5                                                                        4-HO.sub.2 CC.sub.6 H.sub.4                                                             CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7                                               m.p. 102-104° C.              1B     C.sub.6 H.sub.5                                                                        4-HO.sub.2 CC.sub.6 H.sub.4                                                             C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                           m.p. 226-228° C.              1C     4-H.sub.2 NC.sub.6 H.sub.4                                                             C.sub.6 H.sub.5                                                                         C.sub.10 H.sub.21 C(CH.sub.3).sub.2                                                          FAB (M+1)=423                        1D     4-H.sub.2 NC.sub.6 H.sub.4                                                             C.sub.6 H.sub.5                                                                         Δ.sup.7 -cis-C.sub.16 H.sub.31CH(CH.sub.3)                                             FAB (M+1)=491                        1E     C.sub.6 H.sub.5                                                                        4-H.sub.3 COC.sub.6 H.sub.4                                                             C.sub.10 H.sub.21C(CH.sub.3).sub.2                                                           m.p. 110-111° C.              __________________________________________________________________________

EXAMPLE 2 N-[1-Phenyl-2-(4-Aminophenyl)ethyl-α-Phenyl-Benzeneacetamide

To a solution of 2-(4-aminophenyl)-1-phenylethylamine (1.0 g, 4.71mMol), DCC (1.0 g, 4.72 mMol) and DMAP (0.064 g, 0.52 mMol) indichloromethane (100 mL) was added diphenylacetic acid (1.0 g, 4.72mMol). The resulting mixture was stirred 18 hours at room temperature.The mixture was filtered and the precipitate was washed with additionaldichloromethane. The combined filtrates were concentrated and theresulting crude product was purified by chromatography on silica gel,eluting with 1:1 hexane:ethyl acetate to give 1.37 grams of the titlecompound.

EXAMPLE 3 N-[1-Phenyl-2-(4-Aminophenyl)ethyl]-α-Phenyl-Benzeneacetamide

2-(4-aminophenyl)-1-phenylethylamine (0.40 g, 1.9 mMol) anddiphenylacetic acid (0.40 g, 1.9 mMol) were dissolved indimethylformamide (DMF) (4 mL) at room temperature. To this was addedHOBT (0.26 g, 1.9 mMol), NMM (0.19 g, 1.9 mMol) and EDCl (0.36 g) andthe mixture was stirred at room temperature for 18 hours. The DMF wasremoved under vacuum and the oily residue was taken up in 100 mL ethylacetate. The ethyl acetate was washed with saturated sodium bicarbonateand with brine, dried over magnesium sulfate, and evaporated to give0.683 grams of a semi-solid. This was purified on 30 grams offlash-grade silica gel eluting with 100% dichloromethane to give 0.512grams of the title compound, m.p. 161°-163° C.

Using a similar procedure, the following compounds can be prepared:

    __________________________________________________________________________     ##STR24##                                                                    Compound #                                                                           R.sub.1      R.sub.2    R.sub.3           Physical                     __________________________________________________________________________                                                     Data                         3A     4-H.sub.2 NC.sub.6 H.sub.4                                                                 C.sub.6 H.sub.5                                                                          CH.sub.3 (CH.sub.2).sub.14                                                                      200 MHz NMR                                                                   (CDCl3)δ=                                                               0.8-0.93(m, 3H);                                                              1.1-1.31(bs, 26H);                                                            1.45-1.64(m, 2H);                                                             2.13(t, 2H, J=8Hz);                                                           2.93(d, 2H, J=7Hz);                                                           3.97(bs, 2H);                                                                 5.17(dt, 1H, J=7,7Hz);                                                        5.63(d, 1H, J=7Hz);                                                           6.58(d, 1H, J=9Hz);                                                           6.8(dd, 1H, J=9,2Hz);                                                         7.11-7.36(m, 6H)             3B     4-H.sub.2 NC.sub.6 H.sub.4                                                                 C.sub.6 H.sub.5                                                                          CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).su                                   b.7               m.p. 77-80° C.        3C     4-H.sub.2 NC.sub.6 H.sub.4                                                                 C.sub.6 H.sub.5                                                                          n-C.sub.9 H.sub.19                                                                              m.p. 105-107° C.      3D     4-H.sub.2 NC.sub.6 H.sub.4                                                                 C.sub.6 H.sub.5                                                                          nC.sub.5 H.sub.11 m.p. 120-121° C.      3E     4-H.sub.2 NC.sub.6 H.sub.4                                                                 C.sub.6 H.sub.5                                                                          n-C.sub.11 H.sub.23                                                                             m.p. 103-104° C.      3F     4-H.sub.2 NC.sub.6 H.sub.4                                                                 C.sub.6 H.sub.5                                                                          4-ClC.sub.6 H.sub.4CH(4-ClC.sub.6 H.sub.4)                                                      m.p. 187-188° C.      3G     C.sub.6 H.sub.5                                                                             ##STR25## CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).su                                   b.7               m.p. 80-83° C.        3H     3-H.sub.2 NC.sub.6 H.sub.4                                                                 C.sub.6 H.sub.5                                                                          C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              m.p. 140-144° C.      3I     4-H.sub.2 NC.sub.6 H.sub.4                                                                 C.sub.6 H.sub.5                                                                           ##STR26##        m.p. 109-115° C.      3J     C.sub.6 H.sub.5                                                                             ##STR27## C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              m.p. 145-148° C.      3K     4-H.sub.2 NC.sub.6 H.sub.4                                                                 C.sub.6 H.sub.5                                                                          (CH.sub.3).sub.3 COC(O)NH(CH.sub.2).sub.10                                                      m.p. 89-90° C.        3L     4-H.sub.2 NC.sub.6 H.sub.4                                                                 C.sub.6 H.sub.5                                                                          (CH.sub.3).sub.3 COC(O)NH(CH.sub.2).sub.11                                                      m.p. 78-82° C.        3M     C.sub.6 H.sub.5                                                                             ##STR28## CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).su                                   b.7               m.p. 121-123° C.      3N     4-FC.sub.6 H.sub.4                                                                          ##STR29## CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).su                                   b.7               m.p. 95-97° C.        3O                                                                                    ##STR30##   C.sub.6 H.sub.5                                                                          C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              m.p. 166-189° C.      3P     C.sub.6 H.sub.5                                                                             ##STR31## C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              m.p. 184-186° C.      3Q     C.sub.6 H.sub.5                                                                             ##STR32## CH.sub.3 (CH.sub.2).sub.7CH(CH.sub.2).sub.7                                                     m.p. 67-69° C.        3R     4-FC.sub.6 H.sub.4                                                                          ##STR33## C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              m.p. 196-198° C.      3S     C.sub.6 H.sub.5                                                                             ##STR34## C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              m.p. 152-153° C.      3T     4-H.sub.2 NC.sub.6 H.sub.4                                                                 C.sub.6 H.sub.5                                                                          C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              FAB (M+1)=473                3U                                                                                    ##STR35##   C.sub.6 H.sub.5                                                                          CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).su                                   b.7               m.p. 53-54° C.        3V                                                                                    ##STR36##   C.sub.6 H.sub. 5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              m.p. 164-165° C.      3W     C.sub.6 H.sub.5                                                                            4-H.sub.3 COC.sub.6 H.sub.4                                                              C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              m.p. 173-174° C.      3X     C.sub.6 H.sub.5                                                                            4-H.sub.3 COC.sub.6 H.sub.4                                                              CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).su                                   b.7               m.p. 91-93° C.        3Y     4-H.sub.2 NC.sub.6 H.sub.4                                                                 C.sub.6 H.sub.5                                                                          C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)CH.sub.2                                                      m.p. 161-162° C.      3Z     4-H.sub.3 COC.sub.6 H.sub.4                                                                4-H.sub.3 COC.sub.6 H.sub.4                                                              C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              m.p. 190-193° C.      3AA    4-H.sub.3 COC.sub.6 H.sub.4                                                                4-H.sub.3 COC.sub.6 H.sub.4                                                              CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).su                                   b.7               m.p. 116-118° C.      3BB    4-H.sub.2 NC.sub.6 H.sub.4                                                                 C.sub.6 H.sub.5                                                                          C.sub.6 H.sub.5CH.sub.2CH(C.sub.6 H.sub.5)                                                      FAB (M+1)=407                3CC    C.sub.6 H.sub.5                                                                            4-H.sub.2 NC.sub.6 H.sub.4                                                               C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              m.p. 160-162° C.      3DD                                                                                   ##STR37##   C.sub.6 H.sub.5                                                                          C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              m.p. 181-183° C.      3EE                                                                                   ##STR38##   C.sub.6 H.sub.5                                                                          C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              m.p. 156-158° C.      3FF    4-H.sub.3 COC.sub.6 H.sub.4 -m.p.                                                          C.sub.6 H.sub.5                                                                          C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              m.p. 169-171° C.      3GG                                                                                   ##STR39##   C.sub.6 H.sub.5                                                                          C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              m.p. 123-123.5°                                                        C.                           3HH                                                                                   ##STR40##   C.sub.6 H.sub.5                                                                          C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                                                              m.p. 116-117°         __________________________________________________________________________                                                     C.                       

EXAMPLE 4α-Phenyl-N-[1-Phenyl-2-(4-Hydroxyphenyl)ethyl]-Benzeneacetamide

The product of Example 3FF (66.1 mg, 157 mMol) was treated with borontribromide (0.32 mMol, 0.32 mL of a 1M solution) in dichloromethane at0° C. for 1.5 hours. The reaction was quenched with saturated sodiumbicarbonate and the reaction mixtures extracted into dichloromethane.The dichloromethane was washed with water and brine, dried overmagnesium sulfate, and evaporated. The residue was purified by silicagel chromatography, eluting with 1:1 hexane:ethyl acetate to obtain 53mg of the title compound. Elemental analysis: calc for C₂₈ H₂₅ NO₂ isC=81.32%, H=6.26%, N=3.39%; Found C=81.28%, H=6.08%, N=3.25%.

EXAMPLE 4A

Using a procedure similar to that of Example 4, treat the product ofExample 3W to obtainα-phenyl-N-[1-(4-hydroxyphenyl)-2-phenylethyl]-benzeneacetamide, m.p.67°-69° C.

EXAMPLE 5N-[12-[[2-(4-Aminophenyl)-1-Phenylethyl]amino]-12-Oxododecyl]-α-Phenyl-Benzeneacetamide

To1,1-dimethylethyl-12-[[2-(4-aminophenyl)-1-phenylethyl]amino]-12-oxododecylcarbamate(5.2 g, 10.5 mMol) in 80 mL dioxane at 0° C. was added 25 mL saturatedHCl in dioxane. The mixture was allowed to come to room temperaturewhile stirring overnight. The solvent was removed under vacuum and thecrude product was acylated with diphenyl acetic acid according to theprocedure of Example 3 to obtain the title compound, m.p. 107°-114° C.

EXAMPLE 5A

Using a procedure similar to Example 5, treat1,1-dimethylethyl-11-[[2-(4-aminophenyl)-1-[phenylethyl]amino]-11-oxoundecylcarbamateto obtainN-[11-[[2-(4-aminophenyl)-1-phenylethyl]amino]-11-oxoundecyl]-α-phenyl-benzeneacetamide,m.p. 96°-102° C.

EXAMPLE 6

Treat the product of Example 3A with lCl to obtainN-(1-oxo-hexadecanyl)-1-phenyl-2-(3-iodo-4-aminophenyl)ethyl amine.Elemental analysis: calc for C₃₀ H₄₅ IN₂ O is C=79.95%, H=10.29%,N=6.22%; found C=79.87%, H=10.51%, N=6.34%.

EXAMPLE 7

Carry out a basic hydrolysis of the product of Example 3DD to obtain thecorresponding free acid,N-[1-phenyl-2-(4-carboxyphenyl)ethyl]-α-phenyl-benzeneacetamide, m.p.245°-248° C.

EXAMPLE 8

Treat the product of Example 3 with methanesulfonylchloride to obtainN-[1-phenyl-2-(4-methanesulfonylaminophenyl)ethyl]-α-phenyl-benzeneacetamide,m.p. 200°-202° C.

EXAMPLE 9

Acetylate the product of Example 3 with acetic anhydride/pyridine toobtainN-[1-phenyl-2-(4-acetamidophenyl)ethyl]-α-phenyl-benzeneacetamide, m.p.247°-249° C.

EXAMPLE 10 (-)N-[1-Phenyl-2-(4-Aminophenyl)Ethyl]-α-Phenyl-Benzeneacetamide

Using the (-) 2-(4-aminophenyl)-1-phenylethylamine of Preparation 7,follow the procedure of Example 2 to obtain the title compound, [α]D²⁶=-1.9° C. (MeOH).

Similarly, starting with (+) 2-(4-aminophenyl)-1-phenylethylamine,prepare (+)N-[1-phenyl-2-(4-aminophenyl)ethyl]-α-phenyl-benzeneacetamide, [α]D²⁶=+2.1° C. (MeOH).

The following formulations exemplify some of the dosage forms of thisinvention. In each the term "active compound" designates a compound offormula I, preferably(-)-N-[1-phenyl-2-(4-aminophenyl)ethyl]-α-phenyl-benzeneacetamide.However, this compound may be replaced by an equally effective amount ofother compounds of formula I.

EXAMPLE A Tablets

    ______________________________________                                        No.   Ingredient         mg/tablet mg/tablet                                  ______________________________________                                        1     Active Compound    100       500                                        2     Lactose USP        122       113                                        3     Corn Starch, Food Grade, as a                                                                     30        40                                              10% paste in Purified Water                                             4     Corn Starch, Food Grade                                                                           45        40                                        5     Magnesium Stearate  3         7                                               Total              300       700                                        ______________________________________                                    

Method of Manufacture

Mix Item Nos. 1 and 2 in suitable mixer for 10-15 minutes. Granulate themixture with Item No. 3. Mill the damp granules through a coarse screen(e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Screen thedried granules if necessary and mix with Item No. 4 and mix for 10-15minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture toappropriate size and weight on a suitable tablet machine.

EXAMPLE B Capsules

    ______________________________________                                        No.    Ingredient        mg/tablet mg/tablet                                  ______________________________________                                        1      Active Compound   100       500                                        2      Lactose USP       106       123                                        3      Corn Starch, Food Grade                                                                          40        70                                        4      Magnesium Stearate NF                                                                            4         7                                                Total             250       700                                        ______________________________________                                    

Method of Manufacture

Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. AddItem No. 4 and mix for 1-3 minutes. Fill the mixture into suitabletwo-piece hard gelatin capsules on a suitable encapsulating machine.

We claim:
 1. A compound represented by the formula ##STR41## wherein R₁and R₂ are independently X-substituted phenyl, wherein X is 1 to 3substituents independently selected from the group consisting ofhalogeno, lower alkyl, hydroxy, lower alkoxy, amino, lower alkylamino,lower dialkylamino, acetamido, methanesulfonylamino, carboxy and loweralkoxycarbonyl;and in addition, one of R₁ and R₂ can be as defined aboveand the other can be phenyl; R₃ is a diphenyl substituted alkyl chain of1 to 25 carbon atoms, branched or straight, saturated or containing oneor more double bonds; or --(CH₂)₇ CH═CH(CH₂)₇ CH₃ ; R₄ is hydrogen,lower alkyl, phenyl, or X-substituted phenyl;or a pharmaceuticallyacceptable salt thereof.
 2. A compound of claim 1 wherein R₄ ishydrogen.
 3. A compound of claim 2 wherein --C(O)R₃ is oleoyl,diphenylacetyl, 2,2-diphenylpropanoyl, or 2,3-diphenylpropanyl.
 4. Acompound of claim 3 wherein --C(O)R₃ is diphenylacetyl or oleoyl.
 5. Acompound of claim 1 wherein R₁ is amino-substituted phenyl and R₂ isphenyl.
 6. A compound of claim 1 wherein R₁ and R₂ are each loweralkoxy-substituted phenyl or one of R₁ and R₂ is loweralkoxy-substituted phenyl and the other is phenyl.
 7. A compound ofclaim 1 wherein one of R₁ and R₂ is carboxy-substituted phenyl or loweralkoxycarbonyl-substituted phenyl and the other is phenyl.
 8. A compoundof claim 1 wherein one of R₁ and R₂ is hydroxy-substituted phenyl andthe other is phenyl or each of R₁ and R₂ is hydroxy-substituted phenyl.9. A compound of claim 6 wherein --C(O)R₃ is diphenylacetyl or oleoyl.10. A compound of claim 7 wherein --C(O)R₃ is diphenylacetyl or oleoyl.11. A compound of claim 8 wherein --C(O)R₃ is diphenylacetyl or oleoyl.12. A compound of claim 1 which is(-)N-[1-phenyl-2-(4-aminophenyl)ethyl]-α-phenyl-benzeneacetamide.
 13. Apharmaceutical composition useful for treating atherosclerosiscomprising an ACAT-inhibitory effective amount of a compound of claim 1in a pharmaceutically effective carrier.
 14. A compound of claim 1represented by the formula:

    __________________________________________________________________________     ##STR42##                                                                    wherein                                                                       Formula                                                                            R.sub.1     R.sub.2   R.sub.3                                            __________________________________________________________________________    1A   C.sub.6 H.sub.5                                                                           4-HO.sub.2 CC.sub.6 H.sub.4                                                             CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7                                1                                                  1B   C.sub.6 H.sub.5                                                                           4-HO.sub.2 CC.sub.6 H.sub.4                                                             C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 2,3  4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 3B   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7                                1                                                  3H   3-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 3O                                                                                  ##STR43##  C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 3T   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 3W   C.sub.6 H.sub.5                                                                           4-H.sub.3 COC.sub.6 H.sub.4                                                             C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 3X   C.sub.6 H.sub.5                                                                           4-H.sub.3 COC.sub.6 H.sub.4                                                             CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7                                4                                                  3Y   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)CH.sub.2         3Z   4-H.sub.3 COC.sub.6 H.sub.4                                                               4-H.sub.3 COC.sub.6 H.sub.4                                                             C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 3AA  4-H.sub.3 COC.sub.6 H.sub.4                                                               4-H.sub.3 COC.sub.6 H.sub.4                                                             CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7                                .                                                  3BB  4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH.sub.2CH(C.sub.6 H.sub.5)         3CC  C.sub.6 H.sub.5                                                                           4-H.sub.2 NC.sub.6 H.sub.4                                                              C.sub.6 H.sub. 5CH(C.sub.6 H.sub.5)                3DD                                                                                 ##STR44##  C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 3FF  4-H.sub.3 COC.sub.6 H.sub.4                                                               C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 4    4-OHC.sub.6 H.sub.4                                                                       C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 4A   C.sub.6 H.sub.5                                                                           4-OHC.sub.6 H.sub.4                                                                     C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 7    HOOCC.sub.6 H.sub.4                                                                       C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 8    CH.sub.3 SO.sub.2 NHC.sub.6 H.sub.4                                                       C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 9    CH.sub.3 CONHC.sub.6 H.sub.4                                                              C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 __________________________________________________________________________


15. A method of treating atherosclerosis comprising administering to amammal in need of such treatment a pharmaceutical composition comprisingan ACAT-inhibitory affective amount of a compound represented by theformula ##STR45## wherein R₁ and R₂ are independently X-substitutedphenyl, wherein X is 1 to 3 substituents independently selected from thegroup consisting of halogeno, lower alkyl, hydroxy, lower alkoxy, amino,lower alkylamino, lower dialkylamino, acetamido, methanesulfonylamino,carboxy and lower alkoxycarbonyl;and in addition, one of R₁ and R₂ canbe as defined above and the other can be phenyl; R₃ is an alkyl chain of1 to 25 carbon atoms, branched or straight, saturated or containing oneor more double bonds; an alkyl chain as defined substituted by one ormore substituents selected from the group consisting of phenyl andX-substituted phenyl; an alkyl chain as defined interrupted by one ormore groups independently selected from the group consisting of --O--,--S--, --SO--, --SO₂ --, --NH--, --N(lower alkyl)--, --C(O)--, phenyleneand X-substituted phenylene; or an interrupted alkyl chain as definedsubstituted by one or more substituents selected form the groupconsisting of phenyl and X-substituted phenyl; R₄ is hydrogen, loweralkyl, phenyl or X-substituted phenyl;or a pharmaceutically acceptablesalt thereof, in a pharmaceutically acceptable carrier.
 16. A methodaccording to claim 15 wherein the compound administered is representedby the formula ##STR46## wherein

    __________________________________________________________________________    Formula                                                                            R.sub.1     R.sub.2   R.sub.3                                            __________________________________________________________________________    1    4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         Δ7-cis-C.sub.16 H.sub.31 C(CH.sub.3).sub.                               2                                                  1A   C.sub.6 H.sub.5                                                                           4-HO.sub.2 CC.sub.6 H.sub.4                                                             CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7                                6                                                  1B   C.sub.6 H.sub.5                                                                           4-HO.sub.2 CC.sub.6 H.sub.4                                                             C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 1C   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         C.sub.10 H.sub.21 C(CH.sub.3).sub.2                1D   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         Δ.sup.7 -cis-C.sub.16 H.sub.31 CH(CH.sub.                               3)                                                 1E   C.sub.6 H.sub.5                                                                           4-H.sub.3 COC.sub.6 H.sub.4                                                             C.sub.10 H.sub.21 C(CH.sub.3).sub.2                2,3  4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 3A   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         CH.sub.3 (CH.sub.2).sub.14                         3B   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7     3C   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         n-C.sub.9 H.sub.19                                 3D   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         nC.sub.5 H.sub.11                                  3E   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         n-C.sub.11 H.sub.23                                3F   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         4-ClC.sub.6 H.sub.4CH(4-ClC.sub.6 H.sub.4)         3H   3-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 3I   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                          ##STR47##                                         3K   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         (CH.sub.3).sub.3 COC(O)NH(CH.sub.2).sub.10         3L   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         (CH.sub.3).sub.3 COC(O)NH(CH.sub.2).sub.11         3O                                                                                  ##STR48##  C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 3T   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 3W   C.sub.6 H.sub.5                                                                           4-H.sub.3 COC.sub.6 H.sub.4                                                             C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 3X   C.sub.6 H.sub.5                                                                           4-H.sub.3 COC.sub.6 H.sub.4                                                             CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7     3Y   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)CH.sub.2         3Z   4-H.sub.3 COC.sub.6 H.sub.4                                                               4-H.sub.3 COC.sub.6 H.sub.4                                                             C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 3AA  4-H.sub.3 COC.sub.6 H.sub.4                                                               4-H.sub.3 COC.sub.6 H.sub.4                                                             CH.sub.3 (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7     3BB  4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH.sub.2CH(C.sub.6 H.sub.5)         3CC  C.sub.6 H.sub.5                                                                           4-H.sub.2 NC.sub.6 H.sub.4                                                              C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 3DD                                                                                 ##STR49##  C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 3FF  4-H.sub.3 COC.sub.6 H.sub.4                                                               C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 4    4-OHC.sub.6 H.sub.4                                                                       C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 4A   C.sub.6 H.sub.5                                                                           4-OHC.sub.6 H.sub.4                                                                     C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 5    4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         (C.sub.6 H.sub.5).sub.2 C(O)NH(CH.sub.2).sub.11    5A   4-H.sub.2 NC.sub.6 H.sub.4                                                                C.sub.6 H.sub.5                                                                         (C.sub.6 H.sub.5).sub.2 C(O)NH(CH.sub.2).sub.10          ##STR50##  C.sub.6 H.sub.5                                                                         H.sub.3 C(CH.sub.2).sub.14                         7    HOOCC.sub.6 H.sub.4                                                                       C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 8    CH.sub.3 SO.sub.2 NHC.sub.6 H.sub.4                                                       C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 9    CH.sub.3 CONHC.sub.6 H.sub.4                                                              C.sub.6 H.sub.5                                                                         C.sub.6 H.sub.5CH(C.sub.6 H.sub.5)                 __________________________________________________________________________